Aldosterone antagonists (spironolactone, eplerenone)
Serious hyperkalemia if renally impaired, gynecomastia (less with eplerenone)
Angioedema, renal failure, hypotension, hyperkalemia, hepatitis, neutropenia,
cough, rashes, taste disturbance
Rarely angioedema (38% cross-reaction if h/o angiotensin-converting enzyme
inhibitor angioedema), hepatitis, headache, dizziness, fatigue
hypotension, bradycardia, decompensated heart failure,
CNS effects (lipophilic agents > nonlipophilic: depression, psychosis,dizziness, weakness, fatigue, vivid dreams, insomnia),
Reduced peripheral vascular perfusion,
Beta-blockers slow the heart and can depress the myocardium; they are contra-indicated in patients with second- or third-degree heart block. Beta-blockers should also be avoided in patients with worsening unstable heart failure; care is required when initiating a beta-blocker in those with stable heart failure
Ca2+ channel blockers
Hypotension, bradycardia (verapamil, diltiazem), worsening of heart failure
symptons (verapamil, diltiazem), dizziness, flushing, peripheral edema,
constipation, postural hypotension, taste disturbances
cetrally acting agents
Withdrawal hypertension, hypotension, hepatitis (methyldopa), bradycardia
(clonidine), frequent CNS effects (depression, sedation), GI effects, sexual
dysfunction, xerostomia (clonidine)
Cardiovascular effects (heart block, ectopic arrhythmias, ventricular extra
beats, ventricular tachycardia, paroxysmal supraventricular tachycardia),
GI effects (anorexia, nausea, vomiting, diarrhea), CNS effects (drowsiness,
dizziness, confusion, vision abnormalities, photophobia)
direct thrombin inhibitors
lepirudin argatroban bivalirudin
Bleeding (no available antidote for reversal), allergic reaction to reexposure and antibody formation (lepirudin)
Hypotension, hepatitis, neuropathy, flushing, GI effects, LLS (lupus like symptoms)
Dehydration, hypokalemia, hyponatremia, pancreatitis, jaundice, deafness (high dose), thrombocytopenia, serious skin disorders, dizziness, postural hypotension, gout
Dose-related hypotension, headache, renal impairment, increased mortality
Syncope, TIAs, headache, flushing, palpitations, peripheral edema
of potassium sparing diuretics
Hyperkalemia, dehydration, GI effects (nausea, vomiting, diarrhea), CNS
effects (headache, weakness), rashes, gynecomastia in men and breast
enlargement/soreness in women (spironolactone)
Dehydration, rarely thrombocytopenia, cholestatic jaundice, pancreatitis, hepatic
encephalopathy (in patients with cirrhosis), dizziness, gout, hyperglycemia,
orthostasis, hypokalemia, hypermagnesemia, hypercalcemia, GI effect
Abnormal bleeding, rarely necrosis or gangrene of skin and other tissues, purple
toe syndrome (cholesterol microembolization), osteoporosis
Management of stable angina
Acute attacks of stable angina should be managed with sublingual glyceryl trinitrate
Patients with stable angina should be given a beta-blocker OR a Ca2+-channel blocker.
In those with LV dysfunction, beta-blocker treatment should be started at a very low dose and titrated very slowly over a period of weeks or months
the rate-limiting Ca-channel blockers, diltiazem and verapamil, are contra-indicated in patients with LV dysfunction because they may precipitate HF.
If a beta-blocker or a Ca-channel blocker alone fails to control symptoms adequately, a combination of a beta-blocker and a dihydropyridine calcium-channel blocker (e.g. amlodipine, felodipine, modified-release nifedipine) should be used;
if this combination is not appropriate due to intolerance of, or contra-indication to, either beta-blockers or calcium-channel blockers, addition of a long-acting nitrate , ivabradine, nicorandil, or ranolazine can be considered.
Specific considerations when using sotalol
Sotalol may prolong the QT interval, and it occasionally causes life-threatening ventricular arrhythmias (important: particular care is required to avoid hypokalaemia in patients taking sotalol).
Beta blockers in phaeochromocytoma
Beta-blockers can be used to control the pulse rate in patients with phaeochromocytoma. However, they should never be used alone as beta-blockade without concurrent alpha-blockade may lead to a hypertensive crisis. For this reason phenoxybenzamine should always be used together with the beta-blocker.
Verapamil is used for the treatment of:
angina , hypertension, and arrhythmias .
highly negatively inotropic calcium channel-blocker and it reduces cardiac output, slows the heart rate, and may impair atrioventricular conduction.
It may precipitate heart failure, exacerbate conduction disorders, and cause hypotension at high doses and should not be used with beta-blockers
. Constipation is the most common side-effect.
Nifedipine relaxes vascular smooth muscle and dilates coronary and peripheral arteries. It has more influence on vessels and less on the myocardium than does verapamil, and unlike verapamil has no anti-arrhythmic activity.
It rarely precipitates heart failure because any negative inotropic effect is offset by a reduction in left ventricular work. Short-acting formulations of nifedipine are not recommended for angina or long-term management of hypertension; their use may be associated with large variations in blood pressure and reflex tachycardia
. Nicardipine has similar effects to those of nifedipine and may produce less reduction of myocardial contractility.
Amlodipine and felodipine also resemble nifedipine and nicardipine in their effects and do not reduce myocardial contractility and they do not produce clinical deterioration in heart failure. They have a longer duration of action and can be given once daily.
Nifedipine, nicardipine, amlodipine, and felodipine are used for the treatment of angina or hypertension.
All are valuable in forms of angina associated with coronary vasospasm.
Side-effects associated with vasodilatation such as flushing and headache (which become less obtrusive after a few days), and ankle swelling (which may respond only partially to diuretics) are common.
Diltiazem is effective in most forms of angina ; the longer-acting formulation is also used for hypertension. It may be used in patients for whom beta-blockers are contra-indicated or ineffective. It has a less negative inotropic effect than verapamil and significant myocardial depression occurs rarely. Nevertheless because of the risk of bradycardia it should be used with caution in association with beta-blockers.
Anti-arrhythmic drugs can be classified clinically into those that act on supraventricular arrhythmias (e.g. verapamil), those that act on both supraventricular and ventricular arrhythmias (e.g. amiodarone), and those that act on ventricular arrhythmias (e.g. lidocaine).
Class I: membrane stabilising drugs (e.g. lidocaine, flecainide)
Class II: beta-blockers
Class III: amiodarone; sotalol (also Class II)
Class IV: calcium-channel blockers (includes verapamil but not dihydropyridines)
Adenosine is usually the treatment of choice for terminating PSVT. A very short duration of action (half-life only about 8 to 10 seconds, but prolonged in those taking dipyridamole), most side-effects are short lived. Unlike verapamil, adenosine can be used after a beta-blocker. Verapamil may be preferable to adenosine in asthma.
Dronedarone is a multi-channel blocking anti-arrhythmic drug; it is licensed for the maintenance of sinus rhythm after cardioversion in clinically stable patients with paroxysmal or persistent atrial fibrillation,
Oral administration of a cardiac glycoside (such as digoxin) slows the ventricular response in cases of atrial fibrillation and atrial flutter. However,IV infusion of digoxin is rarely effective for rapid control of ventricular rate. Cardiac glycosides are contra-indicated in supraventricular arrhythmias associated with accessory conducting pathways (e.g. Wolff-Parkinson-White syndrome).
Verapamil is usually effective for supraventricular tachycardias. An initial intravenous dose (important: serious beta-blocker interaction hazard,) may be followed by oral treatment; hypotension may occur with large doses. It should not be used for tachyarrhythmias where the QRS complex is wide (i.e. broad complex) unless a supraventricular origin has been established beyond reasonable doubt. It is also contra-indicated in atrial fibrillation or atrial flutter associated with accessory conducting pathways (e.g. Wolff-Parkinson-White syndrome)
IV administration of a beta-blocker such as esmolol or propranolol, can achieve rapid control of the ventricular rate.
Drugs for both supraventricular and ventricular arrhythmias
Drugs for both supraventricular and ventricular arrhythmias include amiodarone, beta-blockers (section 2.4), disopyramide, flecainide, procainamide (available from ‘special-order’ manufacturers or specialist importing companies), and propafenone,
Intravenous lidocaine can be used for the treatment of ventricular tachycardia in haemodynamically stable patients (section 2.3.1), and ventricular fibrillation and pulseless ventricular tachycardia in cardiac arrest refractory to defibrillation (section 2.7.3), however it is no longer the anti-arrhythmic drug of first choice.
Drugs for both supraventricular and ventricular arrhythmias include amiodarone, beta-blockers, disopyramide, flecainide, procainamide (available from ‘special-order’ manufacturers or specialist importing companies), and propafenone, see above under Supraventricular and Ventricular Arrhythmias.
Mexiletine is available from ‘special-order’ manufacturers or specialist importing companies for treatment of life-threatening ventricular arrhythmias.
Loop diuretics are used in pulmonary oedema due to left ventricular failure; intravenous administration produces relief of breathlessness and reduces pre-load sooner than would be expected from the time of onset of diuresis. Loop diuretics are also used in patients with chronic heart failure. Diuretic-resistant oedema (except lymphoedema and oedema due to peripheral venous stasis or calcium-channel blockers) can be treated with a loop diuretic combined with a thiazide or related diuretic
Furosemide and bumetanide are similar in activity; both act within 1 hour of oral administration and diuresis is complete within 6 hours so that, if necessary, they can be given twice in one day without interfering with sleep. Following intravenous administration they have a peak effect within 30 minutes. The diuresis associated with these drugs is dose related.
LOOP diuretics CAUTIONS
Hypovolaemia and hypotension should be corrected before initiation of treatment with loop diuretics; electrolytes should be monitored during treatment (see also Potassium Loss, section 2.2). Loop diuretics can exacerbate diabetes (but hyperglycaemia is less likely than with thiazides) and gout. If there is an enlarged prostate, urinary retention can occur, although this is less likely if small doses and less potent diuretics are used initially; an adequate urinary output should be established before initiating treatment
Loop diuretics should be avoided in severe hypokalaemia, severe hyponatraemia, anuria, comatose and precomatose states associated with liver cirrhosis, and in renal failure due to nephrotoxic or hepatotoxic drugs.
Hypokalaemia induced by loop diuretics may precipitate hepatic encephalopathy and coma—potassium-sparing diuretics can be used to prevent this.
High doses of loop diuretics may occasionally be needed; high doses or rapid intravenous administration can cause tinnitus and deafness; high doses of bumetanide can also cause musculoskeletal pain.
Furosemide and bumetanide should not be used to treat gestational hypertension because of the maternal hypovolaemia associated with this condition.
Side-effects of loop diuretics include mild gastro-intestinal disturbances, pancreatitis, hepatic encephalopathy, postural hypotension, temporary increase in serum-cholesterol and triglyceride concentration, hyperglycaemia (less common than with thiazides), acute urinary retention, electrolyte disturbances (including hyponatraemia, hypokalaemia (see section 2.2), hypocalcaemia, hypochloraemia, and hypomagnesaemia), metabolic alkalosis, blood disorders (including bone-marrow depression, thrombocytopenia, and leucopenia), hyperuricaemia, visual disturbances, tinnitus and deafness (usually with high parenteral doses and rapid administration, and in renal impairment), and hypersensitivity reactions (including rash, photosensitivity, and pruritus).
inhibit sodium reabsorption at the beginning of the distal convoluted tubule. They act within 1 to 2 hours of oral administration and most have a duration of action of 12 to 24 hours; they are usually administered early in the day so that the diuresis does not interfere with sleep.
In the management of hypertension a low dose of a thiazide produces a maximal or near-maximal blood pressure lowering effect, with very little biochemical disturbance. Higher doses cause more marked changes in plasma potassium, sodium, uric acid, glucose, and lipids, with little advantage in blood pressure control. Chlortalidone and indapamide are the preferred diuretics in the management of hypertension
Bendroflumethiazide can be used for mild or moderate heart failure; it is licensed for the treatment of hypertension but is no longer considered the first-line diuretic for this indication
Thiazides and related diuretics can exacerbate diabetes, gout, and systemic lupus erythematosus. Electrolytes should be monitored, particularly with high doses, long-term use, or in renal impairment. Thiazides and related diuretics should also be used with caution in nephrotic syndrome, hyperaldosteronism, and malnourishment
Thiazides and related diuretics should be avoided in refractory hypokalaemia, hyponatraemia and hypercalcaemia, symptomatic hyperuricaemia, and Addison's disease.
Thiazides and related diuretics should not be used to treat gestational hypertension. They may cause neonatal thrombocytopenia, bone marrow suppression, jaundice, electrolyte disturbances, and hypoglycaemia; placental perfusion may also be reduced. Stimulation of labour, uterine inertia, and meconium staining have also been reported.
The amount of bendroflumethiazide, chlortalidone, cyclopenthiazide, and metolazone present in milk is too small to be harmful; large doses may suppress lactation. For indapamide and xipamide see individual drugs.
Side-effects of thiazides and related diuretics include mild gastro-intestinal disturbances, postural hypotension, altered plasma-lipid concentrations, metabolic and electrolyte disturbances including hypokalaemia (see also notes above), hyponatraemia, hypomagnesaemia, hypercalcaemia, hyperglycaemia, hypochloraemic alkalosis, hyperuricaemia, and gout. Less common side-effects include blood disorders such as agranulocytosis, leucopenia, and thrombocytopenia, and impotence. Pancreatitis, intrahepatic cholestasis, cardiac arrhythmias, headache, dizziness, paraesthesia, visual disturbances, and hypersensitivity reactions (including pneumonitis, pulmonary oedema, photosensitivity, and severe skin reactions) have also been reported.
Potassium sparing diuretics
Amiloride and triamterene on their own are weak diuretics. They cause retention of potassium and are therefore given with thiazide or loop diuretics as a more effective alternative to potassium supplementAdministration of a potassium-sparing diuretic to a patient receiving an ACE inhibitor or an angiotensin-II receptor antagonist can also cause severe hyperkalaemia.
Spironolactone potentiates thiazide or loop diuretics by antagonising aldosterone; it is a potassium-sparing diuretic. Spironolactone is of value in the treatment of oedema and ascites caused by cirrhosis of the liver; furosemide can be used as an adjunct. Low doses of spironolactone are beneficial in moderate to severe heart failure, see section 2.5.5, and when used in resistant hypertension [unlicensed indication]
Spironolactone is also used in primary hyperaldosteronism (Conn's syndrome). It is given before surgery or if surgery is not appropriate, in the lowest effective dose for maintenance.
Eplerenone is licensed for use as an adjunct in left ventricular dysfunction with evidence of heart failure after a myocardial infarction
Mannitol is an osmotic diuretic that can be used to treat cerebral oedema and raised intra-ocular pressure.
severe cardiac failure; severe pulmonary oedema; intracranial bleeding (except during craniotomy); anuria; severe dehydration
The statins (atorvastatin, fluvastatin, pravastatin, rosuvastatin, and simvastatin) competitively inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, an enzyme involved in cholesterol synthesis, especially in the liver.
Statins are more effective than other lipid-regulating drugs at lowering LDL-cholesterol concentration but they are less effective than the fibrates in reducing triglyceride concentration. However, statins reduce cardiovascular disease events and total mortality irrespective of the initial cholesterol concentration.
The risk of myopathy, myositis, and rhabdomyolysis associated with statin use is rare. Although myalgia has been reported commonly in patients receiving statins, muscle toxicity truly attributable to statin use is rarclose monitoring of liver function and, if muscular symptoms occur, of creatine kinase is necessary.
bile acid sequestrants
Colesevelam, colestipol, and colestyramine are bile acid sequestrants used in the management of hypercholesterolaemia.
They act by binding bile acids, preventing their reabsorption; this promotes hepatic conversion of cholesterol into bile acids;
the resultant increased LDL-receptor activity of liver cells increases the clearance of LDL-cholesterol from the plasma.
Bile acid sequestrants effectively reduce LDL-cholesterol but can aggravate hypertriglyceridaemia.
interfere with the absorption of fat-soluble vitamins; supplements of vitamins A, D, K, and folic acid may be required when treatment is prolonged.
As bile acid sequestrants are not absorbed, gastro-intestinal side-effects predominate. Constipation is common, but diarrhoea has occurred, as have nausea, vomiting, and gastro-intestinal discomfort. Hypertriglyceridaemia may be aggravated. An increased bleeding tendency has been reported due to hypoprothrombinaemia associated with vitamin K deficiency.
Ezetimibe inhibits the intestinal absorption of cholesterol. It is licensed as an adjunct to dietary manipulation in patients with primary hypercholesterolaemia in combination with a statin or alone (if a statin is inappropriate), in patients with homozygous familial hypercholesterolaemia in combination with a statin, and in patients with homozygous familial sitosterolaemia (phytosterolaemia). If ezetimibe is used in combination with a statin, there is an increased risk of rhabdomyolysis
Bezafibrate, ciprofibrate, fenofibrate, and gemfibrozil act mainly by decreasing serum triglycerides; they have variable effects on LDL-cholesterol. Although a fibrate can reduce the risk of coronary heart disease events in those with low HDL-cholesterol or with raised triglycerides, a statin should be used first. Fibrates are first-line therapy only in those whose serum-triglyceride concentration is greater than 10 mmol/litre or in those who cannot tolerate a statin. In type 2 diabetes, fenofibrate can be added to a statin for those with a serum-triglyceride concentration exceeding 2.3 mmol/litre, despite 6 months of treatment with a statin and optimal glycaemic control.
Fibrates can cause a myositis-like syndrome, especially if renal function is impaired. Also, combination of a fibrate with a statin increases the risk of muscle effects (especially rhabdomyolysis) and should be used with caution (see Muscle Effects) and monitoring of liver function and creatine kinase should be considered; gemfibrozil and statins should not be used concomitantly.
The value of nicotinic acid is limited by its side-effects, especially vasodilatation.
In doses of 1.5 to 3 g daily it lowers both cholesterol and triglyceride concentrations by inhibiting synthesis; it also increases HDL-cholesterol. Nicotinic acid is used by specialists in combination with a statin if the statin alone cannot adequately control dyslipidaemia (raised LDL-cholesterol, triglyceridaemia, and low HDL-cholesterol); nicotinic acid can also be used alone if the patient is intolerant of statins (for advice on treatment of dyslipidaemia, including use of combination treatment, see lipid-regulating drugs).